Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry
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The intramembrane proteases Signal-peptide-peptidase-like 2a and b (SPPL2a/b) have distinct functions in vivo

Mol Cell Biol. 2014 Feb 3. [Epub ahead of print]

Authors/Editors: Schneppeneim J
Hüttl S
Mentrup T
Lüllmann-Rauch R
Rothaug M
Engelke M
Dittmann K
Dressel R
Araki M
Araki K
Wienands J
Fluhrer R
Saftig P
Schröder B
Publication Date: 2014
Type of Publication: Journal Article

We reported recently, that the presenilin homologue signal-peptide-peptidase-like 2a (SPPL2a) is essential for B cell development by cleaving the N-terminal fragment (NTF) of the invariant chain (li, CD74). Based on this, we suggested that pharmacological modulation of SPPL2a may represent a novel approach to deplete B cells in autoimmune disorders. With regard to reported overlapping substrate spectra of SPPL2a and its close homologue SPPL2b, we have investigated the role of SPPL2b in CD74 NTF proteolysis and its impact on B and dendritic cell homeostasis. In heterologous expression experiments, SPPL2b was found to cleave CD74 NTF with similar efficiency as SPPL2a. For in vivo analysis, SPPL2b single-deficient and SPPL2a/b double-deficient mice were generated and examined for CD74 NTF turnover/accumulation, B cell maturation and functionality as well as dendritic cell homeostasis. We demonstrate that in vivo SPPL2b does not exhibit a physiologically relevant contribution to CD74 proteolysis in B and dendritic cells. Furthermore, we reveal that both proteases exhibit divergent subcellular localizations in B cells and different expression profiles in murine tissues. These findings suggest distinct functions of SPPL2a and SPPL2b and, based on a high abundance of SPPL2b in brain, a physiological role of this protease in the central nervous system.

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